Cultured skin fibroblasts from patients with I-cell disease exhibit abnormally high intralysosomal levels of free cystine and in this respect are strikingly reminiscent of the characteristic property of cultured cells from individuals affected with the unrelated genetic disorder cystinosis. To determine whether the abnormal cystine levels seen in these two cell types are the result of the same or similar cellular defects, the comparative effects of a number of physical and chemical manipulations on these levels have been compared. The results of these experiments suggest that the elevated levels of free cystine which are characteristic of cystinotic and I-cell fibroblasts may arise from dissimilar cellular abnormalities.